CN101397321A - Preparation of hydrocortisone and derivatives thereof - Google Patents
Preparation of hydrocortisone and derivatives thereof Download PDFInfo
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- CN101397321A CN101397321A CNA2007100612563A CN200710061256A CN101397321A CN 101397321 A CN101397321 A CN 101397321A CN A2007100612563 A CNA2007100612563 A CN A2007100612563A CN 200710061256 A CN200710061256 A CN 200710061256A CN 101397321 A CN101397321 A CN 101397321A
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Abstract
The invention relates to a preparation method of steroids compounds, in particular to the preparation of hydrocortisone and derivatives thereof. The invention adopts 17-hydroxy-4, 9-diene-pregna-3, 20-diketone as the original material which is modified by 21 bits and 9, 11 bits so as to obtain anecortave acetate retaane, the hydrocortisone and hydrocortisone acetate, and the like. The technical process of the invention adopts the existing intermediates of manufacturers as the original material; the route is simple; the feasibility is high; the operability is strong; the materials are available; the use of expensive accessories is avoided so as to largely reduce the cost of industrial manufacturing; a plurality of products can be obtained on the same manufacturing line; the yield and the cost are dramatically better than that of the prior methods used for synthesizing the hydrocortisone and the derivatives thereof; moreover, the adoption of the existing intermediates realizes the combined-line production of triamcinolone acetonide series products, hydrocortisone series products and anecortave acetate series products so as to greatly reduce the manufacturing cost and the conditions for industrial manufacturing; wherein, R is equal to minus OCOR1 and R1 is equal to the alkyl with the carbon less than 11.
Description
Technical field
The present invention relates to a kind of preparation method of steroidal compounds, especially relate to the preparation of hydrocortisone and derivative thereof.
Background technology
Hydrocortisone and derivative thereof are middle effect adrenal cortex hormones drugs, are widely used clinically, and its product has: hydrocortisone, hydrocortisone acetic ester.Hydrocortisone sodium phosphate or the like.Its curative effect and prednisone are suitable, and anti-inflammatory action is stronger, be 3~5 times of cortisone, but the water-electrolyte metabolism effect are very weak, generally are difficult for causing side effects such as Water-Electrolyte disorder.Product has oral preparation and injection at present, also can be used for skin outward.
Hydrocortisone and derivative synthesis technique thereof just have a long time ago, and hydrocortisone the earliest is to take out from the animal adrenal gland body, see document Arch Biochem., 25,457 (1950) and document Science, 112,506 (1950), mainly in the body of ox, extract.The general strong document US 2602769 of Upjohn has adopted biosynthesizing, mainly is 11 methods that go up hydroxyl, utilizes mucormycosis (mucorales fungi) biological fermentation.ZL200410019858 mentions the method for producing hydrocortisone, be starting strain generally with Absidia coerulea (Abasidia coerules) or curvularia lunata (Curvularia lunata), obtain nutrient solution through enlarged culturing, with bacterial culture fluid and reaction substrate RSA, i.e. 17 Alpha-hydroxies-pregnant steroid-4-alkene-3,20-diketone-21-acetic ester places reactor after mixing, and carries out conversion reaction and prepare hydrocortisone under normal pressure.
Mention among the document ZL200410019858.9: under suitable pressure and pressure medium condition, pressure can improve the output of the mould or curvularia lunata fermentative production hydrocortisone of blue colter.
Hydrocortisone chemosynthesis part; see document J.Am.Chem.Soc.72; 5793 (1950); with 20-itrile group-17 pregnene-21-hydroxyl-3, the 11-diketone is a starting raw material, and 3-ketone is carried out the ketal protection; use lithium borohydride that the selective reduction of 11-ketone is the 11-hydroxyl; use perosmic anhydride to 4, dehydrogenation is carried out in the 5-position, obtains hydrocortisone at last under the effect of acetic acid Urea,amino-.
Document ZL92110286.0 has reported the chemical method synthetic route of a preparation hydrocortisone, uses 9 α-halogen-11 β hydroxyl-androstane-4-alkene-3, and the 17-diketone is a starting raw material, obtains hydrocortisone through polystep reaction, and route is as follows:
The synthetic of hydrocortisone mainly is biological fermentation process and chemical synthesis in history, has weak point.At first biological fermentation process is mentioned among the document ZL200410019858.9, in the production of hydrocortisone, exists and produces the problem that yield is low, cost is high, and very low mainly due to the solubleness of steroidal compounds in water, general solubility range is 10
-6-10
-5Mol/L belongs to indissoluble or slightly soluble compound, mainly is present in aqueous phase and participate in the enzyme that 11 beta-hydroxies turn usefulness in the microbe, is again a kind of intracellular enzyme in addition, therefore makes the steroidal substrate very difficult with contacting of enzyme.This insoluble of steroidal substrate has had a strong impact on the speed and the productive rate of steroidal conversion reaction just, becomes the rate-limiting reaction in the hydroxylating process.Secondly chemical synthesis part, document 1 J.Am.Chem.Soc.72 in 5793 (1950), uses chemical method 4,5 dehydrogenations, and cost is higher, pollutes bigger.Document 2 ZL92110286.0 routes are longer, used more expensive dithioglycol and protected 3 ketone, and cost is higher, and industrialization degree is not high.
Mention among document world clinical medicine 2006 Vol.27No.7P.406-408, anecortave (anecortaveacetate, Retaane) be a kind of novel vascular formation inhibitor, can effectively suppress choroid neovascularization (CNV) generates, stablize patient's vision. external in recent years multinomial multicenter contrasts clinical studies show at random, reach 6 months its mechanism of action, action time with uniqueness, and security is better, is the new selection of age-related macular degeneration (AMD) patient treatment.
Summary of the invention
At the deficiency on the synthetic method of hydrocortisone and derivative thereof in history, we utilize the technical superiority of my company, a brand-new synthesizing hydrogenated cortisone and derivative operational path thereof have been designed, select 17 Alpha-hydroxies-4,9-diene-pregnant steroid-3,20-diketone (CN1896090) is an initiator, through 21 and 9,11 transformations, obtained NSC 24345, hydrocortisone, products such as hydrocortisone acetate, we are at the advantage of technology: adopting company's existing intermediate is starting raw material, simple in circuits, raw material is easy to get, and does not have expensive auxiliary material, make a route obtain a plurality of products, yield and cost obviously are better than the synthetic method of historical hydrocortisone and derivative thereof; In addition, utilize existing intermediate, make our triamcinolone series product, hydrocortisone series anecortave series product carry out doubling production, production cost and industrialized condition reduce greatly.
The invention provides compound (I), i.e. 17 Alpha-hydroxies-4,9-diene-pregnant steroid-3, the application of 20-diketone in the preparation steroidal compounds.Compound (I) can obtain anecortave 21-carboxylate (III) through after 21 and 9,11 transformations, hydrocortisone-21 carboxylate (V) and hydrocortisone (VI) thereof, and this route is as follows:
R=-OCOR1 wherein, R1=11 the alkyl that carbon is following.
Detailed process is as follows:
(1) goes up Iod R: reactant compound (I) is added in the organic solvent, add iodinating agent, obtain intermediate iodide (II).
(2) replacement(metathesis)reaction: the iodide (II) that step () is obtained add in the organic solvent, add the alkyl carboxylate, obtain anecortave 21-carboxylate (III).
(3) bromination reaction: just in anecortave 21-carboxylate (III) the adding organic solvent that step (two) obtains, add bromide reagent and acid catalyst, the intermediate bromide (IV) that obtains.
(4) debromination: the bromide (IV) that step (three) is obtained adds in the organic solvent, adds reductive agent, and debromination obtains hydrocortisone-21 carboxylate (V).
(5) hydrolysis: hydrocortisone-21 carboxylate (V) that step (four) is obtained adds in the organic solvent, adds alkali, and hydrolysis reaction obtains hydrocortisone (VI).
The organic solvent that step () goes up Iod R comprises lower aliphatic alcohols, as methyl alcohol or ethanol; Ethers, as ether, tetrahydrofuran (THF), dioxane etc.; Halogenated hydrocarbon, as chloroform, methylene dichloride etc. are selected in these organic solvents one or more for use; Particular methanol, methylene dichloride, tetrahydrofuran (THF) and two or more mixed solvents thereof, more preferably methyl alcohol, tetrahydrofuran (THF).Iodination reagent can be selected from the iodine grain, can be mixed with iodine the solution form of organic solvent in the reaction earlier, such as using methyl alcohol and tetrahydrofuran (THF), can add solubility promoter calcium chloride.Reaction process can slowly add iodine liquid, and the temperature of reaction is-10 ℃ to 30 ℃, preferred-5 ℃ to 20 ℃.
The organic solvent of step (two) replacement(metathesis)reaction comprises lower aliphatic alcohols, as methyl alcohol or ethanol; Amides is as dimethyl formamide; Ethers, as ether, tetrahydrofuran (THF), dioxane; Heterocyclic, as pyridine, pyrazoles etc., preferred dimethyl formamide, pyridine add the alkyl carboxylic acid reactant salt and obtain in the reaction, alkyl carboxylate's structural formula is A (OCOR5) n, A is a metal ion, and n is the valence number of metal ion A, and R5 is an alkyl, wherein A can be selected from basic metal, alkaline-earth metal, III main group metal, the preferred sodium ion of A, potassium ion, calcium ion; R5 can select 12 carbon with interior alkyl, and preferred 5 carbon are with interior alkyl, the preferred Potassium ethanoate of alkyl carboxylate, calcium acetate, Sodium Propionate, calcium propionate, potassium butyrate, valeric acid potassium.Also to add organic acid in the reaction, preferred organic carboxyl acid, such as acetate, propionic acid.Preferably see which type of alkyl carboxylate A (OCOR5) n of reaction needed, select corresponding carboxylic acid HOCOR5, A and R5 definition are as above.The temperature of reaction is-10 ℃ to 100 ℃, preferred 30 ℃ to 80 ℃.
The organic solvent of step (three) bromination reaction comprises lower aliphatic alcohols, as methyl alcohol or ethanol; Ketone is as acetone; Ethers, as ether, tetrahydrofuran (THF), dioxane etc.; Select in these organic solvents one or more for use; Preferred acetone, ether, tetrahydrofuran (THF) and two or more mixed solvents thereof, more preferably acetone, tetrahydrofuran (THF).Bromide reagent can be selected from bromide reagent, such as using the dibromo malonamide nitrile, dibromo cyano group propionic acid amide, C5H6Br2N2O2, N-bromo ethanamide, N-bromo phthalic diamide, N-bromosuccinimide (NBS), preferred dibromo malonamide nitrile, N-bromosuccinimide (NBS).Acid catalyst is optional from organic acid, mineral acid, such as: hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, formic acid, acetate or the like, preferred perchloric acid.Temperature of reaction is selected from-10 ℃ to 30 ℃, preferred 0 ℃ to 20 ℃.
The organic solvent of step (four) debromination comprises lower aliphatic alcohols, as methyl alcohol or ethanol; Ketone is as acetone; Amides is as dimethyl formamide; Ethers, as ether, tetrahydrofuran (THF), dioxane etc. are selected in these organic solvents one or more for use; Preferred dimethyl formamide, tetrahydrofuran (THF).The reductive agent that uses can be metallic reducing agents such as divalence chromic salts, chromic salt, tributyltin hydride, iron powder, zinc powder, nickel powder, glass putty, preferred divalence chromic salts, chromic salt, tributyltin hydride, glass putty, nickel powder.Temperature of reaction-10 ℃ is to 80 ℃, preferred-5 ℃ to 60 ℃.
Step (five) hydrolysis reaction organic solvent comprises lower aliphatic alcohols, as methyl alcohol or ethanol; Halogenated hydrocarbon, as chloroform, methylene dichloride; Ethers, as ether, tetrahydrofuran (THF), dioxane etc.; Select in these organic solvents one or more for use; Particular methanol, methylene dichloride, tetrahydrofuran (THF) and two or more mixed solvents thereof, more preferably methyl alcohol, methylene dichloride.
Alkali can be selected: sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood or the like, preferred sodium hydroxide.The adding mode of alkali is preferably certain density solution form.Temperature of reaction is selected from-10 ℃ to 40 ℃, preferred-5 ℃ to 10 ℃.
Compound (I) is preparing on the steroidal compounds, wherein preferred R=-OCOR1, R1=5 the alkyl that carbon is following.
Compound (I) on the preparation steroidal compounds, more preferably R=-OCOR1 wherein, R1=CH3.Can obtain three important steroidal compounds products in this case, be respectively: NSC 24345, hydrocortisone acetate and hydrocortisone.
Undoubtedly, the anecortave 21-carboxylate (III) that obtains among the present invention through 21 hydrolysis reaction, can be obtained anecortave; The hydrocortisone that obtains is carried out 21 bit esterifiedly can obtain a series of hydrocortisones-21-carboxylate; The hydrocortisone that just obtains carries out 17 bit esterifiedly can obtain a series of hydrocortisones-17-carboxylate, as hydrocortisone butyrate.
The last Iod R that the present invention relates to mainly is the reaction that iodine replaces 21-position hydrogen atom, the primary product of this reaction is two iodine substitution products, see above and mention all iodide, Iod R can obtain a spot of single iodine thing on these, but single iodine thing can not have influence on next step reaction, a spot of single iodine thing also can participate in the replacement(metathesis)reaction of back, and mechanism wherein is referring to patent US4440689.
Brand-new steroidal compounds operational path provided by the invention has following advantage:
(1) technology is simple and direct, and raw material is easy to get, and does not have expensive auxiliary material, and yield is higher.
(2) feasibility height, strong operability, each goes on foot intermediate and all can obtain by general chemical method purification.
(3) triamcinolone series product, hydrocortisone series anecortave series product have carried out doubling production, and production cost and industrialized condition reduce greatly.
Embodiment
Below will the invention will be further described by embodiment, these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, still belong within protection scope of the present invention.
Embodiment one
Two iodo-17 Alpha-hydroxies-4 of last Iod R: 21-, 9-diene-pregnant steroid-3,20-diketone;
Add methyl alcohol 150ml in the reaction flask, calcium oxide 6g, in the other volumetric flask with 90ml methanol solution Calcium Chloride Powder Anhydrous 8.2g, molten clear back takes out 1/4, adds in the reaction flask, and surplus person is dissolved iodine grain 15g, 17 Alpha-hydroxies-4 that add 10g in the reaction flask, 9-diene-pregnant steroid-3,20-diketone (CN1896090), inflated with nitrogen, temperature control drip iodine solution in 0 ± 5 ℃, dripped off in about 3 hours, after reacting 1 hour again, reaction solution is diluted in 2% aqueous ammonium chloride solution of 600ml and dilutes, stirred 1 hour, left standstill 1 hour, filter, be washed to neutrality, obtain wet product iodide (II), this product instability, drying-free, storage period is unsuitable long, stand-by.
Replacement(metathesis)reaction: 17 α, 21-dihydroxyl 4,9-diene-pregnant steroid-3,20-diketone-21-acetic ester
Add DMF50ml in the reaction flask, acetic acid 1ml, Potassium ethanoate 0.9g adds iodide (II), and the chamber is stirred after 1 hour and was warming up to 35 ℃ of restir 1 hour, rising to 60 ± 2 ℃ afterwards again stirred 2 hours, reduce to room temperature, pour in the 500ml saturated sodium-chloride water and dilute, with 40ml chloroform extraction product three times, merge organic phase, after being washed to neutrality, concentrate, pour ethyl ester during small volume, separate out solid, 0 ± 2 ℃ left standstill 2 hours, filtered, a small amount of ethyl ester washing material, drying, the anecortave 21-acetic ester of 10.2g.
Bromination reaction: 9 α-bromo-11 β, 17 α, 21-trihydroxy--4-pregnene-3,20-diketone-21-acetic ester;
The anecortave 21-acetic ester that in reaction flask, adds 10.2g, the tetrahydrofuran (THF) of 50ml stirs, cool to 0 ℃, in 30 minutes, add dibromo malonamide nitrile 6.5g, remain on 5-10 ℃ and reacted 1 hour down, add the 10% sodium bicarbonate aqueous solution PH=6.5 that neutralizes, be diluted in the water, filter drying, obtain 9 α-bromo-11 β of 11.8g, 17 α, 21-trihydroxy--4-pregnene-3,20-diketone-21-acetic ester.
Debromination: 11 β, 17 α, 21-trihydroxy--4-pregnene-3,20-diketone-21-acetic ester;
9 α-bromo-11 β that add 11.8g in the reaction flask, 17 α, 21-trihydroxy--4-pregnene-3,20-diketone-21-acetic ester, DMF100ml, logical nitrogen, 80~90 ℃ of heating temperature controls splash into reductive agent 20ml tributyltin hydride fast, react after 1 hour, be cooled to 30 ℃, pour in the 800ml saturated nacl aqueous solution and dilute, stirred 1 hour, left standstill 1 hour, and filtered, be washed to neutrality, drying obtains hydrocortisone-21-acetic ester (V) of 9.5g.
Hydrolysis reaction: hydrocortisone
Add 30ml methyl alcohol and 30ml methylene dichloride in the reaction flask, hydrocortisone-21-the acetic ester (V) that adds 9.5g, logical nitrogen cools to 0 ℃, in 1 hour, splash into 18ml 2% NaOH/ methanol solution, keep 0-5 ℃ of temperature, reacted 2 hours, add an amount of acetic acid and be neutralized to PH=7, concentrating under reduced pressure, recrystallization in the methyl alcohol obtains the hydrocortisone of 8.0g, MP:215-220 ℃.
Embodiment two
Two iodo-17 Alpha-hydroxies-4 of last Iod R: 21-, 9-diene-pregnant steroid-3,20-diketone;
Add tetrahydrofuran (THF) 50ml in the reaction flask, calcium oxide 6g, in the other volumetric flask with 90ml methanol solution Calcium Chloride Powder Anhydrous 8.2g, molten clear back takes out 1/4, adds in the reaction flask, and surplus person is dissolved iodine grain 15g, 17 Alpha-hydroxies-4 that add 10g in the reaction flask, 9-diene-pregnant steroid-3,20-diketone (CN1896090), inflated with nitrogen, temperature control drip iodine solution in 0 ± 5 ℃, dripped off in about 3 hours, after reacting 1 hour again, reaction solution is diluted in 2% aqueous ammonium chloride solution of 600ml and dilutes, stirred 1 hour, left standstill 1 hour, filter, be washed to neutrality, obtain wet product iodide (II), this product instability, drying-free, storage period is unsuitable long, stand-by.
Replacement(metathesis)reaction: 17 α, 21-dihydroxyl-4,9-diene-pregnant steroid-3,20-diketone-21-propionic ester
Add DMF50ml in the reaction flask, propionic acid 1.2ml, Sodium Propionate 0.9g adds iodide (II), and the chamber is stirred after 1 hour and was warming up to 35 ℃ of restir 1 hour, rising to 60 ± 2 ℃ afterwards again stirred 2 hours, reduce to room temperature, pour in the 500ml saturated sodium-chloride water and dilute, with 40ml chloroform extraction product three times, merge organic phase, after being washed to neutrality, concentrate, pour ethyl ester during small volume, separate out solid, 0 ± 2 ℃ left standstill 2 hours, filtered, a small amount of ethyl ester washing material, drying, the anecortave 21-propionic ester of 10.6g.
Bromination reaction: 9 α-bromo-11 β, 17 α, 21-trihydroxy--4-pregnene-3,20-diketone-21-propionic ester;
The anecortave 21-propionic ester that in reaction flask, adds 10.6g, the acetone of 100ml stirs, cool to 0 ℃, in 30 minutes, add N-bromosuccinimide 9.5g, remain on 5-10 ℃ and reacted 1 hour down, add the 10% sodium bicarbonate aqueous solution PH=6.5 that neutralizes, be diluted in the water, filter drying, obtain 9 α-bromo-11 β of 12.5g, 17 α, 21-trihydroxy--4-pregnene-3,20-diketone-21-propionic ester.
Debromination: 11 β, 17 α, 21-trihydroxy--4-pregnene-3,20-diketone-21-propionic ester;
The configuration reductive agent: get 10g chromium grain in reaction flask, logical nitrogen adds concentrated hydrochloric acid 10ml, and normal-temperature reaction 30 minutes is standby.
9 α-bromo-11 β that in the another one reaction flask, add 12.5g, 17 α, 21-trihydroxy--4-pregnene-3,20-diketone-21-propionic ester, 60ml dimethyl formamide, logical nitrogen, cool to 10 ℃, slowly add the chromium reducing agent that configures, reacted 30 minutes, filter, filtrate is diluted in the water, filter, drying obtains hydrocortisone-21-propionic ester (V) of 10.3g.
Hydrolysis reaction: hydrocortisone
Add 30ml methyl alcohol and 30ml methylene dichloride in the reaction flask, hydrocortisone-21-the propionic ester (V) that adds 10.3g, logical nitrogen cools to 0 ℃, in 1 hour, splash into 20ml 2% NaOH/ methanol solution, keep 0-5 ℃ of temperature, reacted 2 hours, add an amount of acetic acid and be neutralized to PH=7, concentrating under reduced pressure, recrystallization in the methyl alcohol obtains the hydrocortisone of 8.1g, MP:215-220 ℃.
Claims (4)
1. the application of compound (I) in the preparation steroidal compounds, it is characterized in that compound (I) through after 21 and 9,11 transformations, obtains anecortave 21-carboxylate (III), hydrocortisone-21 carboxylate (V) and hydrocortisone (VI) thereof, this route is as follows:
R=-OCOR1 wherein, R1=11 the alkyl that carbon is following.
Detailed process is as follows:
(1) goes up Iod R: reactant compound (I) is added in the organic solvent, add iodinating agent, obtain intermediate iodide (II);
(2) replacement(metathesis)reaction: the iodide (II) that step () is obtained add in the organic solvent, add the alkyl carboxylate, obtain anecortave 21-carboxylate (III);
(3) bromination reaction: just in anecortave 21-carboxylate (III) the adding organic solvent that step (two) obtains, add bromide reagent and acid catalyst, the intermediate bromide (IV) that obtains;
(4) debromination: the bromide (IV) that step (three) is obtained adds in the organic solvent, adds reductive agent, and debromination obtains hydrocortisone-21 carboxylate (V);
(5) hydrolysis: hydrocortisone-21 carboxylate (V) that step (four) is obtained adds in the organic solvent, adds alkali, and hydrolysis reaction obtains hydrocortisone (VI).
2. compound as claimed in claim 1 (I) is characterized in that at the operational path of preparation steroidal compounds:
The organic solvent that step () goes up Iod R comprises lower aliphatic alcohols, ethers, and halogenated hydrocarbon is selected in these organic solvents one or more for use; Iodination reagent can be selected from the iodine grain, can be mixed with iodine the solution form of organic solvent in the reaction, and the temperature of reaction is selected from-10 ℃ to 30 ℃;
The organic solvent of step (two) replacement(metathesis)reaction comprises lower aliphatic alcohols, amides, ethers, pyridine, pyrazoles; Alkyl carboxylate's structural formula is A (OCOR5) n, and A is a metal ion, and n is the valence number of metal ion A, and R5 is an alkyl, and wherein A can be selected from basic metal, alkaline-earth metal, III main group metal; R5 can be selected from 12 carbon with interior alkyl; Will add organic acid in the reaction, the temperature of reaction is selected from-10 ℃ to 100 ℃;
The preferred lower aliphatic alcohols of organic solvent of step (three) bromination reaction, ketone, ethers is selected in these organic solvents one or more for use; The preferred dibromo malonamide nitrile of bromide reagent, dibromo cyano group propionic acid amide, C5H6Br2N2O2, N-bromo ethanamide, N-bromo phthalic diamide, N-bromosuccinimide; Acid catalyst is optional from organic acid, mineral acid; Preferred-10 ℃ to 30 ℃ of temperature of reaction;
The organic solvent of step (four) debromination comprises lower aliphatic alcohols, ketone, and amides, ethers is selected in these organic solvents one or more for use; Reductive agent can be selected from divalence chromic salts, chromic salt, tributyltin hydride, iron powder, zinc powder, nickel powder or glass putty; Temperature of reaction is selected from-10 ℃ to 80 ℃;
The organic solvent of step (five) hydrolysis reaction comprises lower aliphatic alcohols, halogenated hydrocarbon, and ethers is selected in these organic solvents one or more for use; Alkali is selected from: sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood; The adding mode of alkali is preferably certain density solution form, and temperature of reaction is selected from-10 ℃ to 40 ℃.
3. compound as claimed in claim 1 (I) is at the operational path of preparation steroidal compounds, the alkyl below the preferred R=-OCOR1, R1=5 carbon.
4. compound as claimed in claim 1 (I) is at the operational path of preparation steroidal compounds, more preferably R=-OCOR1, R1=CH3.
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